Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• New oxazolidinone derivatives processes for their preparation and medicaments containing these compounds
• the present invention relates to new oxazolidinone derivatives, processes for their preparation and medicaments which contain these substances
• oxazolidinone derivatives effectively inhibit the aggregation of the blood cells and can therefore be used for the treatment of diseases which are attributable to thromboembolic events, such as stroke, myocardial infarction or arterial occlusive diseases. as well as inflammation, osteoporosis or tumor diseases
• the present invention relates to compounds of the general formula I
• R -, R2 independently of one another are hydrogen, lower alkyl or aryl, or together form a carbocyclic five- or six-membered ring
• R 3 is hydrogen or a group -OR- ⁇ or -NR.6R7
• R ⁇ is hydrogen or a group -OR- '
• R5 denotes hydrogen, lower alkyl, aryl or arylalkyl
• R ⁇ is hydrogen, lower alkyl or arylalkyl
• R ⁇ denotes hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl,
• R ⁇ , - (- » 00 independently of one another are hydrogen, lower alkyl, aryl, arylalkyl, hetaryl, acyl or an optionally substituted carbocyclic or heterocyclic ring, or together with the nitrogen to which they are attached, an optionally substituted five- or six-membered ring Form a ring, which can also contain 1 to 3 further heteroatoms, or a group
• R000 is hydrogen, lower alkyl, arylalkyl or a group NHR 0000
• ROOOO is hydrogen, lower alkyl, arylalkyl, acyl, alkylsulfonyl or arylsulfonyl, and their pharmacologically acceptable salts
• lower alkyl is intended to represent a straight-chain or branched C * -C 6 -alkyl group such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, propyl, isobutyl and pentyl
• Aryl generally means the optionally mono- or polysubstituted phenyl radical
• Arylalkyl usually means an unsubstituted or mono- or poly-substi- wholesome benzyl, phenethyl, phenylpropyl, phenylbutyl or Phenylpentylrest, preferred wise a benzyl, phenethyl or Phenylpentylrest substituents are Cj - Cg-alkyl, preferably methyl, ethyl or isopropyl, and chlorine.
• Acyl generally means the formyl, acetyl, propionyl, butyryl or benzoyl radical, in particular the acetyl or benzoyl radical
• Alkylsulfonyl generally means methanesulfonyl, ethanesulfonyl, propanesulfonyl or the butanesulfonyl radical, in particular the butanesulfonyl radical
• Arylsulfonyl usually means the benzene or toluenesulfonic acid residue
• radicals R ⁇ and R- ⁇ together form a carboclyclic five- or six-membered ring, it is a saturated or unsaturated 5-6-membered ring, which is monosubstituted or disubstituted by lower alkyl, such as the cyclopentyl, cyclohexyl, , Cyclopentenyl or cyclohexenyl ring.
• Preferred compounds are compounds of the formula I in which the group AB represents a group (CH 2 ) ⁇ _3 or (CH 2 ) ⁇ _3-CO and E, G, Q, W, X, Y, Z, D.
• R 1 , R 2 and R 4 have the meaning given
• A-B is the group methylene, ethylene, carbonyl or methylenecarbonyl and E, G, Q, W, X, Y and Z are nitrogen
• R 1 , R 2 , R 3 , R 4 , A, B, E, G, Q, W, X, Y, Z and m have the meanings given above and R ⁇ is methyl, ethyl tert-butyl, phenyl or Benzyl means manufactured
• Carbonyl synthon L ' generally means phosgene, diphosgene, triphosgene, carbonyldiimidazole, dimethyl carbonate or diphenyl ester , Methyl or ethyl chloroformate, in particular carbonyldimidazole, diethyl carbonate or ethyl chloroformate MN-, means a metal azide such as lithium, sodium, potassium, tributin or magnesium azide, in particular lithium or sodium azide TMSN-- the abbreviation for trimethylsilylazide
• L generally means a leaving group such as chlorine, bromine, iodine, mesylate, triflate or
• Tosylate especially chlorine or tosylate
• R-, R 2 , R-, R, A, B and L have the meanings given above and in the event that B is the carbonyl group, L can also be the hydroxyl group; p means the number 1 or 2.
• R% R 2 , A and B have the meanings given above and M has the meaning of a metal such as lithium, magnesium or titanium.
• R 2 , A, B and p have the meanings given above, R ⁇ butyl, phenyl or p-tolyl and Hal "means chloride. Bromide or iodide
• R 1, R 2 , A, B and L have the meanings given above, produce.
• the compounds of the general formula XII are generally commercially available pipecoline carboxylic acid derivatives; in special cases, compounds of the formula XII by reacting a commercially available 3- or 4-piperidone of the formula XXIV,
• hydrolysis of an ester of the general formula II to the corresponding carboxylic acid of the general formula I is carried out by customary processes, in which a carboxylic acid ester of the general formula II in water or in a mixture of water, tetrahydrofuran, dioxane, methanol or ethanol preferably in a water / tetrahydrofuran mixture with a hydroxide such as sodium, potassium or lithium hydroxide, preferably sodium or lithium hydroxide, or with an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably trifluoroacetic acid and at temperatures between room temperature and 80 ° C, preferably at room temperature
• reaction of a compound of general formula XIII with 1-benzylpiperazine or 4-hydroxy- or 4-oxopiperidine (Scheme 2) or the reaction of a compound of formula XI with a compound of formula XII or a compound of formula XI with an amine of the formula XII is usually carried out in an aprotic solvent such as toluene, tetrahydrofuran, diethyl ether, dimethylformamide or methylene chloride, preferably dimethylformamide or tetrahydrofuran using a base such as potassium hydride, sodium hydride, potassium carbonate or sodium hydrogen carbonate, preferably sodium hydride or potassium carbonate and at temperatures between room temperatures and 180 ° C, preferably at 120 ° C or room temperature
• a ketone of the formula XVI with dibenzylamine or an amine of the formula XXX is carried out by processes known from the literature by reacting the ketone and amine components in a solvent such as methanol or ethanol in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoborohydride with the addition of a Bronsted or Lewis acid like hydrochloric acid.
• a solvent such as methanol or ethanol
• a reducing agent such as sodium cyanoborohydride or sodium triacetoborohydride
• a hydrogenation catalyst such as platinum dioxide and a hydrogen atom
• nitrosation of a compound of the general formula XIV to a compound of the formula XV is generally carried out with sodium nitrite or isoamine nitrite in water or ethanol with the addition of an acid such as hydrochloric acid or acetic acid and at a temperature between -20 ° C. and 80 ° C., preferably at room temperature, by
• a nitroso compound of the general formula XV takes place according to known processes in that a compound of the formula XV in a solvent such as water, acetic acid, ethanol, tetrahydrofuran or diethyl ether, preferably acetic acid or tetrahydrofuran with a reducing agent such as elemental zinc, lithium aluminum hydride or Sodium aluminum hydride, preferably elemental zinc or lithium aluminum hydride and at a temperature between room temperature and 120 ° C, but preferably at 70 ° C.
• a reducing agent such as elemental zinc, lithium aluminum hydride or Sodium aluminum hydride, preferably elemental zinc or lithium aluminum hydride and at a temperature between room temperature and 120 ° C, but preferably at 70 ° C.
• the conversion of a compound of the general formula XV into a compound of the formula IV can also be hydrogenolytic with the connection of a catalyst such as palladium / carbon (Hatt.
• the Wittig reaction is carried out according to known methods by refluxing the reactants in an aprotic solvent such as benzene, toluene or xylene, preferably toluene
• Phthalimide hydrolysis is generally carried out by known processes by treating the phthalimide with hydrazine hydrate or semi-concentrated mineral acid such as hydrochloric acid or sulfuric acid, preferably with hydrazine hydrate or hydrochloric acid at room temperature
• the acylation of amines is usually carried out in a solvent such as methylene chloride, dimethylformamide or pyridine, preferably methylene chloride or pyridine with the addition of an auxiliary base such as triethylamine or 4-dimethylaminopyridine and preferably at a temperature between -10 ° C and 50 ° C at room temperature by.
• a solvent such as methylene chloride, dimethylformamide or pyridine, preferably methylene chloride or pyridine
• an auxiliary base such as triethylamine or 4-dimethylaminopyridine
• an olefin of the formula VII or the formula X or the formula XXIII is carried out by processes known from the literature by reacting it with a peracid such as m-chloroperbenzoic acid, peracetic acid or trifluoroperacetic acid, preferably m-chloroperbenzoic acid, in an aprotic solvent such as methylene chloride and at a temperature between -30 ° C and 50 ° C, preferably room temperature, furthermore the olefins mentioned above can be converted into the corresponding epoxides by means of the Sharpless epoxidation (Sharpless KB, Org Syntheses, Vol 63, 66 (1985))
• the organometallic reaction mentioned in Scheme 3 is usually the Grignard reaction, which is carried out according to methods known from the literature.
• the magnesium reagent of the formula XXI can optionally be converted into a lithium or titanium reagent before it is reacted with a carbonyl compound of the formula VI is implemented (Reetz M T., Chem Ber H8, 1421 (1985))
• An amino alcohol of the formula III is converted into an oxazolidinone of the formula II by processes known from the literature by reacting an amino alcohol of the formula III with diethyl carbonate (Evans DA, Org Syntheses, Vol 68, 77 (1989)) or carbonyldiimidazole (Chadwick DI, J. Chem Soc. Perkin Trans 481 (1984), Geffken D Arch Pharm 3J3, 817 (1980)) or phosgene (Newman WS, J Am Chem Soc.
• the catalytic hydrogenation of a compound of the formula XXVII is carried out in a solvent such as methanol or ethanol with the addition of a catalyst such as ruthenium oxide, rhodium oxide or palladium / strontium carbonate, preferably rhodium oxide in a hydrogen atmosphere at a pressure of 1-200 bar, preferably at 200 bar and a temperature between room temperature and 200 ° C by (Rastin RH, I. Chem. Soc. 1855 (1949).
• the epoxy opening of an epoxide of the formula V with an amine of the formula IV generally takes place in a solvent such as methanol, ethanol, dimethylformamide or toluene, preferably ethanol or toluene and at a temperature between 0 ° C. and 120 ° C., preferably 80 ° C. .
• a solvent such as methanol, ethanol, dimethylformamide or toluene, preferably ethanol or toluene and at a temperature between 0 ° C. and 120 ° C., preferably 80 ° C. .
• the epoxy opening of an epoxide of formula V with a metal azide is carried out according to methods known from the literature by reacting an epoxide of formula V with a metal azide such as lithium, sodium, potassium, tributyltin or magnesium azide, preferably sodium azide, in a solvent such as Methanol, ethanol, 1,4-dioxane, water, dimethylformamide, tetrahydrofuran, acetonitrile or hexamethylphosphoric triamide, or in mixtures of the solvents mentioned, but preferably in methanol, dimethylformamide or 1,4-dioxane-water mixtures and in one reaction ⁇ temperature between -10 ° C and 120 ° C, preferably 80 ° C (Vanderverf CA., J.
• a metal azide such as lithium, sodium, potassium, tributyltin or magnesium azide, preferably sodium azide
• a solvent such as Methanol, ethanol, 1,4-dioxane,
• reaction of an epoxide of the formula V with trimethylsilyl azide usually takes place in a solvent such as methanol, tetrahydrofuran, methylene chloride, chloroform, dichloroethane or benzene, preferably tetrahydrofuran or methylene chloride, without further additives or using additives such as titanium tetraisopropylate, aluminum triisopropylate, dichloro- titanium diisopropylate or diethylaluminum fluoride, preferably titanium tetraisopropylate or aluminum triisopropylate and at a temperature between 0 ° C.
• a solvent such as methanol, tetrahydrofuran, methylene chloride, chloroform, dichloroethane or benzene, preferably tetrahydrofuran or methylene chloride
• Racemates of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates can be mechanically or chemically separated into the enantiomers by methods known per se.
• the racemic mixture is preferably reacted with an optically active one Acid such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid diastereomers
• optically active compounds of the formula I by the methods described above by using starting materials (for example those of the formula II) which are already optically active
• the pharmacologically acceptable salts used are primarily alkali metal salts, ammonium salts, trifluoroacetates or hydrochlorides, which are customarily used, for example, by titration of the compounds with inorganic or organic bases or acids such as sodium or potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous ammonia or amines such as, for B produces trimethyl- or triethylamine, trifluoroacetic acid or hydrochloric acid.
• the salts are usually purified by falling over from water / acetone
• novel substances of the formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form.
• Chen application forms for example tablets, capsules, dragees, syrups, solutions, suspensions, etc.
• Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers
• Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control.
• Complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts
• high molecular weight polymers such as liquid polyethylene oxide
• Liquid carrier substances for injection solutions must be sterile and are preferably filled into ampoules.
• Solid carrier substances are, for example, strong, lactose.
• Mannitol methyl cellulose, talc, highly disperse silica, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers (such as polyethylene glycols), preparations suitable for oral application can, if desired, taste and contain sweeteners
• the dosage can depend on various factors, such as the route of administration, species, age and / or individual condition.
• the daily doses to be administered are approximately 10-1000 mg / person, preferably 100-500 mg / person, and can be distributed all at once or several times to be taken
• Microtiter plates were coated overnight with 2 ⁇ g / ml isolated activated GpIIb / IIIa receptor. After the unbound receptor was removed by a few washing steps, the surface of the plate was blocked with 1% casein and washed again. The test substance was added in the necessary concentrations The plates were then incubated for 10 minutes under rubble in a linear shuttle. The natural ligand of the gpIIb / IIIa receptor, fibronogen, was added. After incubation for 1 hour, the unbound fibrinogen was removed by several washing steps and the bound fibronogen was determined.
• the GpIIb / IIIa fibrinogen ELISA is a modification of the assay described in the following references

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